Evidence-based recommendations for optimal dietary protein intake in older people: a position paper from the prot-age study group. Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids (The National Academies Press, 2005).īauer, J. Amino acid sensing by mTORC1: intracellular transporters mark the spot. Mechanism of arginine sensing by CASTOR1 upstream of mTORC1. Sestrin2 is a leucine sensor for the mTORC1 pathway. High-protein diets increase cardiovascular risk by activating macrophage mTOR to suppress mitophagy. Dietary Proteins and Atherosclerosis 1st edn (Taylor & Francis, 2003). Rabbit models for the study of human atherosclerosis: from pathophysiological mechanisms to translational medicine. These data demonstrate a mechanistic basis for the adverse impact of excessive dietary protein on cardiovascular risk.įan, J. By designing specific diets modified in protein and leucine content representative of the intake in the general population, we confirm this threshold effect in mouse models and find ingestion of protein in excess of ∼22% of dietary energy requirements drives atherosclerosis in male mice. We describe a threshold effect of high protein intake and circulating leucine on monocytes/macrophages wherein only protein in excess of ∼25 g per meal induces mTOR activation and functional effects. In a series of clinical studies on male and female participants ( NCT03946774 and NCT03994367) that involved graded amounts of protein ingestion together with detailed plasma amino acid analysis and human monocyte/macrophage experiments, we identify leucine as the key activator of mTOR signalling in macrophages. High protein intake is common in western societies and is often promoted as part of a healthy lifestyle however, amino-acid-mediated mammalian target of rapamycin (mTOR) signalling in macrophages has been implicated in the pathogenesis of ischaemic cardiovascular disease. Nature Metabolism volume 6, pages 359–377 ( 2024) Cite this article Identification of a leucine-mediated threshold effect governing macrophage mTOR signalling and cardiovascular risk
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